Lens crystallins are structural proteins that constitute over 90% of the dry mass of the lens. The crystallins from cataracts are extensively damaged by oxidation, a factor thought to be critical in the etiology of lens opacification. This laboratory is working toward elucidation of the actual functions of crystallins in the normal lens. We are studying how normal lens function is affected by modification of crystallin structure (eg, by oxidation) or by change in the composition of crystallins. We are attempting to elucidate the molecular mechanism causing congenital cataract in guinea pigs with a mutation in the zeta-crystallin gene. Zeta-crystallin is of additional interest because it is an enzyme/crystallin or a protein that apparently has two completely distinct functions. An NADPH: quinone oxidoreductase in certain non-lens tissues, zeta is expressed at very high levels in lens, where it apparently is a structural protein. With both the gene and protein structures characterized, we can examine the role zeta plays in lens opacification, as well as the regulatory mechanisms involved in its elevated lens-specific expression. Oxidation is a major factor in aging-related cataractogenesis, and developing means of preventing oxidation in the lens is a very promising approach to therapeutically preventing cataract. One such approach would be to alter the redox potential of the lens. We have found that lenses from certain species have such a change owing to their very high content of NADPH, a strong reductant. Evaluation of the possible beneficial effects to these lenses is in progress to determine whether attempts to devise means to produce a similar redox potential change in lenses at risk for cataract would be warranted.